overview of funded research on mers-cov · 2019-02-26 · 3 overview of funded research on mers-cov...

Overview of Funded Research

on MERS-CoV

Middle East Respiratory Syndrome – Coronavirus (MERS-CoV)

October 2015

2

Overview of Funded Research on MERS-CoV October, 29 2015

Table of contents

1. EU Funded Research (October 2015) ....................................................................................... 2

2. Germany Funded Research (August 2015) ............................................................................... 4

3. Japan Funded Research (October 2015) .................................................................................. 8

4. U.S. Government Funded Research (September 2015) ............................................................ 9

1. EU FUNDED RESEARCH (OCTOBER 2015)

Of the projects described below, only SILVER has currently made a tangible and significant

contribution to MERS research. E-com@EU has used MERS as an example for risk perception,

success and failures of communication strategies in epidemics. VIROGENESIS is a very new H2020

project on virus discovery that will work on many different viruses, MERS just being one example of

many. PREPARE is an important project on the clinical management of patients in the case of

emerging epidemics in Europe, but it has not worked yet on MERS since there is not currently an

epidemic in Europe.

SILVER 1 (Small-molecule Inhibitor Leads Versus Emerging and neglected RNA

viruses) is a drug design program to face emerging diseases caused by RNA viruses. Around

the end of 2012, the SILVER project activated its outbreak pipeline to address the emerging

MERS‐coronavirus, for which neither vaccination nor antiviral therapy was available. During the

final two years of the SILVER project, nine SILVER partners with different backgrounds and

expertise (virology, bioinformatics, enzymology, structural biology, and medicinal chemistry)

collaborated closely on the characterization of the new virus, the development of a MERS‐CoV

toolbox, and the identification and development of inhibitory compounds and strategies.

Despite the inherently unpredictable nature/timing of this outbreak and the fact that the origin

(virus family wise) of new agents cannot be anticipated, and despite the obvious difficulties of

running an outbreak pipeline in nine different locations, it can be concluded that SILVER’s

response was timely and meaningful. Although antiviral drug development in general remains a

time-consuming process, solid leads for further anti-coronavirus research were obtained, trans-

European collaborations were initiated and strengthened, and SILVER contributed to creating a

better starting position to combat this and future zoonotic coronavirus outbreaks.

1 https://www.silver-europe.com/ - FP7 funded project - start: 2010-10-01; end: 2015-03-31 - EU contribution: € 12.000.000

https://www.silver-europe.com/

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E-com@eu2 (Effective Communication in Outbreak Management: development of an

evidence-based tool for Europe). Literature reviews were completed on risk perception.The

success and failures of communication strategies implemented by institutions such as the ECDC

and the CDC during the H1N1 pandemic were analyzed, as well as epidemiological characteristics

of past and current outbreaks (H1N1, MERS) as disease models to create a simulation.

VIROGENESIS 3 (Virus discovery and epidemic tracing from high throughput

metagenomic sequencing). Next-generation sequencing (NGS) analysis pipelines are rapidly

becoming part of the routine repertoire of research, clinical and public health laboratories in the

public sector and private industry. Middle East Respiratory Syndrome-coronavirus (MERS-CoV)

is only one example of the many recent virus discoveries made through analysis of NGS data.

Yet, only a small part of the several millions of short-length sequence fragments generated by

NGS machineries, many of which are expected to be of viral origin, can be analyzed with current

methods in bioinformatics. Even for well-known (pathogenic) viruses, proper epidemiological

analyses are becoming more and more difficult due to the lack of bioinformatics tools that can

handle the large and growing size of datasets.

The VIROGENESIS consortium will overcome the most pressing bioinformatics obstacles to

making full use of NGS by developing a software platform for end-users with tools underpinned

by novel algorithms, models and bioinformatics methods. The speed and flexibility of the tools will

make it possible to run analyses on a daily basis for a variety of subjects, including diagnostics,

phylogeography, phylodynamics and transmission of drug resistance. The tools will be piloted and

incorporated in the many available bioinformatics pipelines and software programs used in the

field. We will make our tools available in a modular, free and open source software platform that

offers opportunities to small and medium enterprises (SMEs) to further exploit this market. The

VIROGENESIS consortium brings together leading European academic institutions, SMEs,

bioinformatics developers, and virology end-users who initiated this project in response to a clear

interest from EMBL, NCBI and the Global Microbial Identifier (GMI) platform.

PREPARE4 (Platform foR European Preparedness Against (Re-)emerging Epidemics)

will implement ‘inter-epidemic’ large-scale clinical studies, patient-oriented pathogenesis studies

and develop novel diagnostics. In addition PREPARE, develops and tests pre-emptive solutions

to bottlenecks that prevent rapid clinical research responses in the face of new infectious disease

threats. The project has the goal of mounting a rapid, coordinated deployment of Europe’s clinical

investigators, within 48 hours of a severe infectious disease outbreak in Europe. PREPARE is

holding regular and, if needed, ad-hoc meetings of its 'Outbreak Research Mode Committee',

which decides about different research response modes and subsequent actions within

PREPARE. This includes the option of rapidly launching clinical trials in the case of new

2 http://ecomeu.info/ - FP7 funded project – start: 2012-02-01; end: 2016-01-31 – EU contribution: € 1 999 607 3 http://www.kuleuven.be/english/research/EU/p/horizon2020/sc/sc1/Virogenesis - Horizon 2020 funded project - start: 01/06/2015; end: 31/05/2018 – EU contribution: € 2.995.968 4 PREPARE - FP7 funded project - start: 2014-02-01; end: 2019-01-31 – EU contribution: € 23 992 375

http://ecomeu.info/

http://www.kuleuven.be/english/research/EU/p/horizon2020/sc/sc1/Virogenesis

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epidemics. For MERS-CoV infections, PREPARE has been in 'Outbreak Research Mobilisation'

Mode (the second of 3 escalations) from 16 May 2014 until 11 November 2014 and continues

now to be in 'Outbreak Research Preparation' mode (the first escalation), but has so far not

decided to launch any clinical trials on MERS-CoV.

ZAPI5 (Zoonosis Anticipation and Preparedness Initiative) aims to develop a universal

platform for the rapid antigenic characterization of pathogens, and the design and surge

production of vaccines and neutralizing reagents against emerging pathogens, in particular

viruses. This platform will build on close collaborative partnerships between human and veterinary

medical institutions, governmental regulatory agencies, expert academic groups and industrial

partners. In addition, this platform aims at ensuring a fast track for the timely registration and

implementation of the control tools as soon as possible after pathogen emergence. ZAPI will

deliver proof-of-concept by focusing on three viruses, representative of currently emerging

infectious pathogens: Schmallenberg virus (SBV), MERS-CoV and Rift Valley fever virus (RVFV).

The development and application of the proposed platform for intervention strategies against

these three viruses will demonstrate its potential as a broadly applicable and synergistic approach

for the rapid characterization and development of control tools against future emerging viruses.

2. GERMANY FUNDED RESEARCH (AUGUST 2015)

Funded by BMBF (German Federal Ministry for Education and Research) - DZIF (German Center for Infection Research)

Outbreaks of emerging pathogens appear suddenly and rapid response is crucial to contain the

spread of the disease. Actions must be taken both to raise the awareness of the public health sector,

and to develop strategies to speed up biomedical research and production of candidate vaccines and

therapeutics. The mission of the Thematic Translational Unit Emerging Infections is to establish a

research infrastructure that contributes to rapid containment of emerging infections and to mitigate

the consequences of such outbreaks for the public. To fulfil this mission, the Thematic Translational

Unit Emerging Infections shall link expert individuals and research groups within three areas covering

the entire response chain: pathogen detection, diagnostics, and clinical management; emergency

vaccines; and broad-range antivirals.

The activity of the Thematic Translational Unit Emerging Infections will:

Improve our ability to rapidly detect unknown pathogens and deploy diagnostics for novel

pathogens

Link DZIF partner hospitals to develop and agree on standardized treatment plans for emerging

disease entities

Shorten the time to availability of novel vaccines against emerging infectious agents by developing

vaccine platform technology for rapid implementation of novel pathogen

5 Total budget: 22 385 918 € (IMI funding: 9 508 688 €, EFPIA in-kind: 9 875 000€); start date: 01/03/2015 – end date: 29/02/2020.

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Examples of Other MERS Related Projects

The development of diagnostic tools together with industrial partners for detection of MERS CoV,

Novel Coronavirus Detection.

Prof. Dr. Christian Drosten, Rheinische Friedrich-Wilhelms-Universität Bonn. For more

information refer to this link: http://www.virology-bonn.de/index.php?id=40

A preclinical bridging study on MVA-MERS-S, an experimental prophylactic vaccine against the

Middle East Respiratory Virus Syndrome

GMP Manufacture and Phase I clinical investigation of MVA-MERS-S, an experimental

prophylactic vaccine against the Middle East Respiratory Virus Syndrome

Prof. Dr. Gerd Sutter, Ludwig-Maximilians-Universität München; 2014–2017,

Related Press Release:

http://www.dzif.de/en/news_media_centre/news_press_releases/view/detail/artikel/coronaviruse

s_getting_to_a_vaccine_as_fast_as_possible/

Corresponding Literature de Groot RJ, Baker SC, Baric RS, Brown CS, Drosten C, Enjuanes L, Fouchier RA, Galiano M,

Gorbalenya AE, Memish ZA, Perlman S, Poon LL, Snijder EJ, Stephens GM, Woo PC, Zaki AM,

Zambon M, Ziebuhr J (2013) Middle East respiratory syndrome coronavirus (MERS-CoV):

announcement of the Coronavirus Study Group. J Virol, 87(14): 7790-7792

Corman VM, Jores J, Meyer B, Younan M, Liljander A, Said MY, Gluecks I, Lattwein E, Bosch BJ,

Drexler JF, Bornstein S, Drosten C, Muller MA (2014) Antibodies against MERS coronavirus in

dromedary camels, Kenya, 1992-2013. Emerg Infect Dis, 20(8): 1319-1322

Corman VM, Olschlager S, Wendtner CM, Drexler JF, Hess M, Drosten C (2014) Performance and

clinical validation of the RealStar MERS-CoV Kit for detection of Middle East respiratory syndrome

coronavirus RNA. J Clin Virol, 60(2): 168-171

Drosten C, Meyer B, Muller MA, Corman VM, Al-Masri M, Hossain R, Madani H, Sieberg A, Bosch

BJ, Lattwein E, Alhakeem RF, Assiri AM,Hajomar W, Albarrak AM, Al-Tawfiq JA, Zumla AI, Memish

ZA (2014) Transmission of MERS-coronavirus in household contacts. N Engl J Med, 371(9): 828-835

Eckerle I, Corman VM, Muller MA, Lenk M, Ulrich RG, Drosten C (2014) Replicative Capacity of

MERS Coronavirus in Livestock Cell Lines. EmergInfect Dis, 20(2): 276-279

Lei J, Mesters JR, Drosten C, Anemuller S, Ma Q, Hilgenfeld R (2014) Crystal structure of the papain-

like protease of MERS coronavirus reveals unusual, potentially druggable active-site features.

Antiviral Res, 109: 72-82

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Memish ZA, Cotten M, Meyer B, Watson SJ, Alsahafi AJ, Al Rabeeah AA, Corman VM, Sieberg A,

Makhdoom HQ, Assiri A, Al Masri M, Aldabbagh S, Bosch BJ, Beer M, Muller MA, Kellam P, Drosten

C (2014) Human infection with MERS coronavirus after exposure to infected camels, Saudi Arabia,

2013. Emerg Infect Dis, 20(6): 1012-1015

Meyer B, Muller MA, Corman VM, Reusken CB, Ritz D, Godeke GJ, Lattwein E, Kallies S, Siemens

A, van Beek J, Drexler JF, Muth D, Bosch BJ, Wernery U, Koopmans MP, Wernery R, Drosten C

(2014) Antibodies against MERS coronavirus in dromedary camels, United Arab Emirates, 2003 and

2013. Emerg Infect Dis, 20(4): 552-559

Muller MA, Corman VM, Jores J, Meyer B, Younan M, Liljander A, Bosch BJ, Lattwein E, Hilali M,

Musa BE, Bornstein S, Drosten C (2014) MERS coronavirus neutralizing antibodies in camels,

Eastern Africa, 1983-1997. Emerg Infect Dis, 20(12): 2093-2095

Meyer B, García-Bocanegra I, Wernery U, Wernery R, Sieberg A, Müller MA, Drexler JF, Drosten C,

Eckerle I. (2015) Serologic assessment of possibility for MERS-CoV infection in equids. Emerg Infect

Dis. 2015 Jan;21(1):181-2

Scheuplein VA, Seifried J, Malczyk AH, Miller L, Höcker L, Vergara-Alert J, Dolnik O, Zielecki F,

Becker B, Spreitzer I, König R, Becker S, Waibler Z, Mühlebach MD (2015): High secretion of

interferons by human plasmacytoid dendritic cells upon recognition of MERS-CoV. J Virol 89: 3859-

3869.

Funded by DFG (German Science Foundation)

Coronaviruses as a paradigm for the transmission interface between wildlife, livestock

and humans

Professor Dr. Christian Drosten, Rheinische Friedrich-Wilhelms-Universität Bonn

Funded since 2014

Project Description

The importance of coronavirus (CoV) host switching and the zoonotic or epidemic potential of CoV

has been underlined by the emergence of a novel CoV in the Arabian Peninsula in 2012, known as

the MERS-CoV. In this project we investigate the complex process of coronavirus host switching,

integrating various disciplines such as animal ecology, epidemiology, as well as molecular virology

and innate immunity research. The objectives in the second working period reflect the new

possibilities created by Ghanaian veterinarians entering the team, as well as the pressing need for

more insight into reservoirs and origins of MERS-CoV. We continue our investigations of diversity and

evolution of CoV in small mammals, working beyond bats in the second working period. We add as a

new component the importance of livestock as potential intermediary hosts through virus and antibody

testing in livestock.

Molecular biology investigations will continue to address the issues of receptor-mediated cell entry

and evasion of the target cell´s interferon defence. In the area of training and capacity building, we

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will continue to provide field training in ecological methodology on site, and add an additional

emphasis on practical skills in molecular biology by intensified training abroad. The overall goal of the

project is to provide a much better insight into the various stages of viral emergence and to interlink

research capacities between the disciplines of ecology and virology, and between investigators in

Germany and Ghana.

Surface glycoproteins of two bat paramyxoviruses: functional characterization and

importance for host switch

Professor Dr. Georg Herrler, Stiftung Tierärztliche Hochschule Hannover, Institut für Virologie

Funded since 2014

Project Description

In recent years, bats have been recognized as a major reservoir for a number of viruses. From time

to time, viruses succeed in crossing the species barriers and cause infections that may be lethal for

the affected humans or animals. Examples are the coronaviruses responsible for the severe acute

respiratory syndrome (SARS) or the Middle East respiratory syndrome (MERS), or the Nipah virus

within the family Paramyxoviridae, genus Henipavirus.

Attempts to detect viral nucleic acid in bats have been quite successful; however, to isolate infectious

virus from bats is still a challenging task. So far, there is not a single report about a successful isolation

of a coronavirus from bats. In this case, the limiting factor appears to be the interaction of the viruses

with receptors on the cell surface. As far as paramyxoviruses are concerned, there were a few

successful virus isolations, though the total number is rather low. This makes it difficult to evaluate

the zoonotic potential of the viruses and the danger for man and animals. However, there have been

two interesting findings recently that allow us to analyze the tropism of bat viruses in more detail and

thus to get a better knowledge about these infectious agents. Nipah-like henipaviruses have been

isolated only in South East Asia. However, genomic RNA has been detected also in African bats.

We have shown for the first time that the surface glycoproteins of an African henipavirus (G and F)

have biological activities. Their ability to induce the formation of syncytia, i.e. multinucleated giant

cells, shows that these glycoproteins have a functional receptor-binding as well as fusion activity. In

the proposed project, we will analyze the biological activities of G and F as well as their ability to

mediate infection in more detail. This knowledge will provide a basis for the successful isolation of an

African henipavirus.The detection of genomic RNA from paramyxoviruses in bats revealed the

presence of a virus that is closely related to mumps virus. With the surface glycoproteins (HN and F)

of this mumps-like bat virus we were also able to induce syncytia formation.

Similar to the above mentioned African henipavirus, we will analyze the biological activities of the two

glycoproteins in more detail. In this case, we will provide the basis for a mutational analysis of the

human mumps virus that will reveal which amino acid exchanges are crucial for the transition of the

human virus to the bat virus.

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3. JAPAN FUNDED RESEARCH (OCTOBER 2015)

AMED funded research on Middle East Respiratory Syndrome – Coronavirus (MERS-CoV)

In response to the MERS outbreak in South Korea in May 2015, AMED provided additional funds to

ongoing MERS research projects to accelerate their outcomes.

The following are about the Japanese research projects that are currently focused on MERS-CoV:

1. Detection of Middle East respiratory syndrome coronavirus using reverse transcription

loop-mediated isothermal amplification (RT-LAMP).

Dr. Shutoku Matsuyama, Department of Virology III, National Institute of Infectious Diseases,

Tokyo, Japan et al.

Dr. Matsuyama is a team member of Dr. Tsutomu Kageyama (Influenza Virus Research Center,

National Institute of Infectious Diseases, Tokyo, Japan), who is a leader of the AMED project

‘Research and development of detection systems for influenza virus, measles virus, rubella virus,

MERS-CoV, and other respiratory viruses’.

Their study developed a novel RT-LAMP (Reverse Transcription-Loop-mediated isothermal

amplification) assay for detecting MERS-CoV using primer sets targeting a conserved

nucleocapsid protein region. The RT-LAMP assay was capable of detecting as few as 3.4 copies

of MERS-CoV RNA, and was highly specific, with no cross-reaction to other respiratory viruses.

Pilot experiments to detect MERS-CoV from medium containing pharyngeal swabs inoculated

with pre-titrated viruses were also performed. The RT-LAMP assay exhibited sensitivity similar to

that of MERS-CoV real-time RT-PCR. (referred to Virology Journal2014 Aug 8, 11:139. K. Shirato,

S. Matsuyama et al.). For the 2015 year, the research team plans to improve the conventional

RT-LAMP method.

2. Middle East respiratory syndrome coronavirus infection mediated by the transmembrane

serine protease TMPRSS2.

Dr. Kazuya Shirato, Department of Virology III, National Institute of Infectious Diseases, Tokyo,

Japan, et al.

Dr. Kazuya Shirato is a member of the team of Dr. Makoto Takeda, Department of Virology III,

National Institute of Infectious Diseases, Tokyo, Japan. They are working on the AMED project

‘Research and Development of Novel Diagnosis and Innovative Treatment for Middle East

Respiratory Syndrome and Emerging Influenza’.

The Middle East respiratory syndrome coronavirus (MERS-CoV) utilizes host proteases for virus

entry into lung cells. In their study, they established Vero cells constitutively expressing type II

transmembrane serine protease (Vero-TMPRSS2 cells) (Shirogane et al., 2008 J Virol 82:8942-

6) that showed large syncytia by MERS-CoV infection.

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By using Vero-TMPRSS2 cells and other cell lines derived from lung assay system, they found as

follows:

1. Vero-TMPRSS2 cells have extreme high susceptibility for MERS-CoV in contrast to non-

TMPRSS2 expressing parental Vero cells.

2. MERS-CoV employs both the cell surface and the endosomal pathway to infect Vero-

TMPRSS2 cells.

3. A single treatment with camostat (TMPRSS2 serine protease inhibitor) is sufficient to block

MERS-CoV entry into a well-differentiated lung-derived cell line.(referred to Journal of Virology

2013 Dec; 87(23): 12552-12561, K. Shirato, S. Matsuyama et al.)

For the 2015 year, the research team plans to create the model animals to develop new ways to

diagnose MERS in the laboratory and to understand the molecular basis of the MERS pathogenic

expression.

4. U.S. GOVERNMENT FUNDED RESEARCH (SEPTEMBER 2015) Activities on Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

Although progress has been achieved in understanding the basic biology of MERS-CoV, preclinical

development and research on potential MERS-CoV medical countermeasures (MCMs) remains

preliminary and significant work is likely to be required before any MCMs will be ready for human

clinical trials. Limited funding is available through the National Institute of Allergy and Infectious

Diseases (NIAID) and the Biomedical Advanced Research and Development Authority (BARDA) for

the preclinical and clinical development for MERS-CoV MCMs. Animal model development had also

steadily advanced with the availability of transgenic mouse models, described below, for early product

candidate screening and modeling of human-like pathogenesis. However, candidate medical

products were only marginally advanced between June, 2014 and April, 2015 (the date of the last in-

depth assessment), and this was largely based on efforts that had already been funded by NIH, or

were undertaken by industry at their own expense.

Major factors hindering progress in the pre-clinical development of MERS-CoV MCMs are the lack of

established animal models for human disease from MERS-CoV infection, limited availability of non-

human primates (e.g. common marmosets), and limited funding for preclinical development of MERS-

CoV MCMs. While some progress has been made in addressing these gaps, more work is needed to

facilitate the availability of potential MERS-CoV MCMs for human clinical trials.

April 2015 Medical Countermeasures Assessment: The Office of the Assistant Secretary

for Preparedness and Response convened a meeting in early April 2015 of subject matter experts

and external stakeholders to review the current status of information on candidate products for

prophylaxis, diagnosis or treatment of human disease. This meeting was timely in light of the

subsequent outbreak of MERS-CoV in South Korea and ongoing outbreaks in Saudi Arabia and

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Jordan. A report was developed, based on the framework of an earlier review and assessment

conducted in June, 2014.

The major recommendations of the assessment are enumerated below:

1. Standardize use of animal models for studying disease pathogenesis and for evaluation of

potential medical countermeasures.

2. Establish a clinical specimen and assay validation panel working group to develop a strategy

for point of care MERS-CoV diagnostics and prioritize the creation of validation panels for use

by commercial partners in MERS-CoV diagnostic development.

3. Ensure that there are sufficient laboratory populations of non-human primates needed to

support preclinical research, with a priority on initiating studies of therapeutics.

4. Accelerate product development of the most promising currently available therapeutic

candidates, to include an immunotherapy and a small molecule antiviral drug compound.

5. Prioritize studies to further the scientific understanding and control of MERS-CoV disease in

humans and animals, including vaccination studies in camels.

6. Develop a standardized clinical trial protocol and partner with an effective clinical trials network

within the Gulf Coast Countries (GCC) to assist in evaluating safety and effectiveness of

therapeutic candidates.

Animal Models: Studies have demonstrated that a number of small animals commonly used as

laboratory animal models (e.g. mice, hamsters, ferrets) are not susceptible to MERS-CoV. As a

result multiple approaches are being taken to develop small animal models including but not

limited to testing of nontraditional species (e.g. mink), passage of virus in animals, engineering of

animal models through rational design (e.g. transgenic animals that express human DPP4, the

MERS-CoV receptor), etc. NHP models that are under development include rhesus macaques

and common marmosets. Major gaps for the NHP models include characterization of the different

MERS-CoV strains, determining and standardizing the optimal viral challenge dose, volume, route

of exposure, and the ability for sequential sampling in marmosets and determining clinical relevant

symptoms. Overall, common marmosets appear to be better suited than rhesus macaques for

therapeutic studies designed to target severe disease given the slightly slower onset of illness

and the longer duration and severity of disease. However, the limited supply and availability of

common marmosets in the U.S. is currently a major barrier to the development of MERS-CoV

MCMs. Large animal models in development include camels and camelids such as alpacas.

These models may be important to help understand the virology and immunology of MERS-CoV

infection in dromedary camels. See Appendix 1 for more details.

In-vitro Diagnostics: The CDC submitted a request for Emergency Use Authorization (EUA) of

an in-vitro diagnostic on May 29, 2013 with data to support the performance of their molecular

assay to detect the MERS-CoV virus in several sample types. On June 5, 2013, FDA granted an

EUA for use of the test by trained technicians in qualified laboratories for testing symptomatic

patients. On June 10, 2014 the EUA was expanded to include the ability to test asymptomatic

contacts after a US returning traveler case. This assay has been made available to multiple public

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health, U.S. Department of Defense (DoD), and World Health Organization (WHO) laboratories

worldwide but is limited in terms of being able to scale up reagents to support a possible surge in

the numbers of infected cases. The lack of FDA-cleared commercial assays is likely due to the

limited availability of samples from infected and recovered patients. A USG working group has

been formed to develop panels of specimens that could be sourced, stored and made available

to diagnostic assay developers to help validate the performance of their devices and support an

EUA. This model has been used previously to generate panels of difficult to source specimens

for Ebola virus diagnostic test developers. Funding such a project will be a major challenge that

needs to be explored.

Therapeutics: There are no candidate products that have been specifically evaluated for

treatment of MERS-CoV patients in well controlled clinical studies. Potential therapeutics for

MERS-CoV patients include approved drugs with non-specific properties such as

immunomodulators (e.g. corticosteroids, intravenous immunoglobulin, interferons), approved

small molecule drugs for other diseases that are being screened for specific activity against

MERS-CoV, small molecule drugs with broad antiviral activity, and new therapies

(immunotherapeutics, other inhibitors) with specific activity against MERS-CoV. Appendix 2

provides an overview of the known MERS-CoV therapeutics pipeline. A limited number of

preclinical studies in MERS-CoV-infected humanized mice and NHPs with candidate therapeutics

have been performed, with more planned. BARDA has established an Interagency Agreement

(IAA) with Rocky Mountain Labs (RML) that provides for the testing of therapeutic candidates for

prophylaxis and efficacy in RML’s published marmoset model. Under this IAA, BARDA will

support a prophylaxis study in September and has lined up additional MERS candidates (both

antibody-based and small molecules) to test, pending the availability of marmosets.

BARDA and FDA participated in the September 9-10, 2015 MERS-CoV Research Initiatives

Workshop, sponsored by the College of Public Health and Health Informatics and King Saud bin

Abdulaziz University for Health Sciences, in Riyadh, Saudi Arabia. The workshop included a

robust discussion of clinical trial design, including the potential for using a common master

protocol to evaluate candidate therapeutics. Representatives of five companies presented

updates on the status of their respective MERS-CoV therapeutic candidates in anticipation of

potential clinical trials.

The goals of the meeting were to:

Engender national and international research collaboration across sectors and disciplines

relevant to MERS-CoV;

Identify specific promising therapeutics to consider for evaluation in the context of

appropriately staged clinical research leading to clinical trials in KSA;

Develop action-oriented research recommendations to fill gaps in knowledge in the prevention

and clinical care of patients with MERS-CoV

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Participants in the meeting agreed that:

A research infrastructure should employ an adaptive design that allows either efficient

sequential or parallel evaluation of treatments, in comparison to a concurrent control group,

ideally taking the form of a randomized, blinded (to the intervention) clinical trial.

While much has already been done, further work towards these evaluations should commence

immediately, including collaborative national and international intellectual, scientific, logistical,

regulatory and financial support.

Meeting participants also identified research gaps related to the natural history, epidemiology,

zoonotic transmission, and diagnosis of MERS-CoV as well as the development of animal models.

Vaccines: NIAID, academic investigators, and several companies have initiated the

development of MERS-CoV candidate vaccines. Appendix 3 provides an overview of the known

MERS-CoV human and animal vaccine pipeline. Most vaccine development approaches are still

in pre-IND evaluation in animal models. They have generally targeted the spike protein of MERS-

CoV and are recombinant subunit, DNA or virus particle vector vaccines. At least four vaccine

candidates have demonstrated immunogenicity in mice using the MERS-CoV Spike (S) protein

as an immunogen, through subunit and/or DNA vaccine platforms.

The Vaccine Research Center (VRC), NIAID, is evaluating two approaches based on the S

protein, an S DNA prime-S1 subunit protein boost regimen and an S1 subunit protein prime-S1

subunit protein boost. Favorable immunogenicity data (generation of high quality neutralizing

antibody) have been generated in mice and in NHP (rhesus macaque) systems, the latter system

showing radiological efficacy after virus challenge. The DNA prime-protein boost approach

elicited responses to a larger number of epitopes, a more favorable T cell response and better

protection.

One live-attenuated MERS-CoV candidate vaccine is in early development. Preliminary studies

for several MERS-CoV vaccine candidates have been initiated and demonstrate immunogenicity

and two have progressed to NHP challenge. One vaccine company (Inovio) is preparing to submit

an IND and anticipates start of a Phase 1 study in 2015. Additionally, a number of MERS-CoV

vaccine candidates are being developed with extramural funding/support from NIAID/DMID.

These include vaccines based on recombinant S protein receptor binding domain, adenovirus-

vectored S protein vaccines and work aimed at developing a modified live vaccine (MLV).

One such MLV deletes an essential gene (E) and is consequently attenuated, being able to

undergo only a single cycle of infection in the host yet providing appropriate immune stimulation

theoretically. These extramural projects are all at a very early stage of development. To further

support vaccine development, VRC/NIAID has developed serological assays (including a panel

of 8 pseudotyped lentivirus reporters for assessing neutralizing antibodies) and reagents

(including neutralizing murine mAbs with specificities to multiple regions of the S protein).

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Animal Models in Development

Organization Species Notes

The University of Iowa

Mouse expressing human DPP4 (from Adenovirus 5 vector)

Transient and localized expression of DPP4. Mild infection. Funding support provided by NIAID.

University of Texas Medical Branch-Galveston

Mouse Knock-in of human DPP4, constitutive promoter

Expression of DPP-4 throughout the animal (including brain). Relentless weight loss and death within days post infection. Virus in the brain.

Regeneron

Mouse Knock-in of human DPP4, natural promoter

Stable expression of human DPP4 under a natural promotor (e.g. limited to the lung). Viral replication and lung pathology observed. Possible lethal phenotype, no virus in the brain.

Utah State University and Icahn School of Medicine

2 x transgenic mouse models

MCM evaluation. Funding support provided by NIAID.

Rocky Mountain Laboratories, NIAID Integrated Research Facility, NIAID

Rhesus Macaque

Macaque DPP4 receptor binds MERS. Infection causes acute localized to widespread pneumonia with transient clinical disease. Similar to mild /moderate human MERS-CoV cases. Advanced medical imaging being used to chart and better characterize disease development as well as to measure potential benefit of MCM. Multiple virus isolates being evaluated. Similar to mild/moderate human MERS-CoV cases.

Rocky Mountain Laboratories, NIAID Integrated Research Facility, NIAID

Marmoset

Marmoset DPP4 receptor binds MERS naturally. Multiple routes of infection used. Similar to more severe human MERS-CoV cases. Lethality is ~20%. Advanced medical imaging being used to chart and better characterize disease development as well as to measure potential benefit of MCM. Multiple virus isolates being evaluated. Disease course was more severe than rhesus but no deaths were observed with either isolate tested.

Rocky Mountain Laboratories, NIAID

Dromedary Camels

Infection studies in a small number of dromedary camels are underway in a large animal BSL3 facility in the U.S.

Lab of Infectious Diseases, NIAID

Rabbit Transient infection, no clinical signs, passaging 4-5 times. Possible enhancement of disease seen upon second challenge.

AutoImmune Technologies

Mink Mink epithelial are permissive to MERS-CoV infection. DMID grant.

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Therapeutics in Development

a) MERS-CoV Small Molecule and Biologics Treatment Candidates

Organization Drug Target MERS Activity Notes

Rocky Mountain Laboratories

Ribavirin + IFN Polymerase + Immunomodulator

Active in Rhesus macaques

Approved for Hepatitis C virus. Compassionate use for MERS

University of Hong Kong/Bayer

Interferon B1b Immunomodulator Active in cell culture

Hemispherix Biopharma

Alferon N Immunomodulator Active in cell culture

Approved for HPV

Romark Laboratories

Nitazoxanide Host functions Active in cell culture

Approved for Cryptospordia and Giardia, not active in all labs

AbbVie Lopinavir Protease Active in cell culture

Approved for HIV

BioCryst Pharmaceuticals

BCX4430 Polymerase Active in cell culture

University of Missouri

SSYA10-001 Helicase Active in cell culture

Small Business Grant

DPP4 Decoy Spike/Binding Binding assay Funding support provided by NIAID.

Small Business Grant

Peptide Inhibitors

Spike/Fusion Binding assay Funding support provided by NIAID.

Loyola University, Chicago, Stritch School of Medicine

Protease Inhibitors

MERS PLpro MERS 3CLpro

Active in cell culture

Funding support provided by NIAID.

Various

FDA Approved Drug Screen Chloroquine and chlorpromazine appear promising

Multiple targets

Active in cell Culture. Chloroquine and chlorpromazine also active in the mouse model

Multiple screening efforts. Funding support for some projects provided by NIAID.

Planet Biotechnology

DPP4-Fc

DPP4-Fc chimera that mimics the MERS-CoV receptor

Active in cell culture

Produced in tobacco

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b) MERS-CoV Immunotherapeutic Treatment Candidates

Organization Drug Development Status

IVIG In clinic

Kingdom of Saudi Arabia Convalescent serum Clinical trials active, not

recruiting6

NCI M336, M337, M338 Live MERS-CoV neutralization; NHP studies

University of Hong Kong MERS-4, MERS-27 Live MERS neutralization

Dana Farber Institute 3B11, 1F8, 3A1, 80R Live MERS neutralization; NHP studies

University of Minnesota Mersmab1 Live MERS neutralization

Regeneron REGN3015, REGN3048

VLP neutralization, efficacy in humanized mice; testing in NHP in July; IND-enabling preclinical tox studies ongoing

Juntendo University 2F9 and YS110 VLP neutralization

Adimab Anti-Spike VLP-neutralization

Integrated Biotherpeutics Anti-Spike VLP neutralization

Sanford Research Polyclonal Mouse and NHP studies; IND enabling preclinical toxicology; Vialed product

Vaccines in Development

a) MERS-CoV Human Vaccine Candidates

Organization (Vaccine type)

Preclinical Immunogenicity

(species)

Preclinical Efficacy (challenge model)

Scale-up Capability/Timing

Novavax (S protein trimer in 40 nm particle; adjuvanted likely)

Mouse-immunogenicity shown (Camel studies being planned)

Yes/≈6 months for manufacture Ph I vaccine

NIAID/VRC (Two candidate vaccine approaches: DNA S prime-S1 protein boost and S1 prime-S1 boost)

Mouse and NHP- immunogenicity shown

NHP (macaque-radiological efficacy shown) (Camel and marmoset studies planned)

Yes, at NIAID

6 https://clinicaltrials.gov/ct2/show/NCT02190799

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Organization (Vaccine type)

Preclinical Immunogenicity

(species)

Preclinical Efficacy (challenge model)

Scale-up Capability/Timing

Inovio (DNA expressing S; electroporation device)

Mouse, NHP and camel immunogenicity shown

NHP (viremia, lung pathology and survival)

Yes, via GMP affiliate.

Greffex (full S expressing, fully deleted Adeno packaging vector; RBD constructs being developed)

Mouse immunogenicity shown

NIAID Supported Extramural Projects (Adeno vector, Recombinant Spike, Live attenuated)

Platform development and mouse immunogenicity

Mouse model development to evaluate vaccine efficacy

New York Blood Center (Receptor-binding domain (RBD)-based MERS subunit vaccine)

Immunogenicity and Protective efficacy in a mouse model, including via nasal delivery

BALB/c mice

b) MERS-CoV Camel Vaccine Candidates

Organization Vaccine Type Camelid Vaccination

Studies (PI)

USG/academic institution consortium

S protein nano-particle /Matrix C adjuvant (baculovirus expressed)

Camel vaccination without active challenge, in Saudi Arabia, Egypt, Qatar, and Mongolia; projected start July 2014

USG/academic institution consortium

Inactivated whole virus See above

Rocky Mountain Laboratories, NIAID

S protein subunit vaccine/Advax adjuvant (baculovirus expressed)

Camel and alpaca vaccination-challenge studies at CSU started in June 2014; analysis in progress

Erasmus University MVA vectored S protein In progress, in Qatar, using a camel infection model

Novavax A.B. (Sweden) S nanoparticles with Matrix C adjuvant

In discussions with KSA Department of Agriculture

overview of funded research on mers-cov · 2019-02-26 · 3 overview of funded research on mers-cov...

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